Perceived effectiveness of PCSK9i-SiRNA therapy and adherence to background statin therapy: real-world analysis of the DAMAGE registry
F Guerra, A Malatesta, N Iacobucci, F Spannella, L Di Vito, I Ciccarelli, L Piangerelli, D Caraceni, L Marinucci, A Stronati, D Contadini, E Paolini, P Grossi, M Alfieri, R SarzaniAbstract
Background
Hypercholesterolemia is a primary driver of cardiovascular disease, affecting approximately 39% of the global population. In developed nations, over 50 million individuals receive lipid-lowering treatments, yet many fail to reach targets. The advent of PCSK9-targeted therapies, including monoclonal antibodies (PCSK9i) and small interfering RNA (inclisiran), has enabled LDL cholesterol reductions of over 50% when added to standard care. However, the introduction of these potent injectables may inadvertently lead to reduced adherence to concomitant oral medications. This multicenter, retrospective study evaluates how changes in background therapy (BT) and statin/ezetimibe adherence influence the real-world LDL-c lowering efficacy of PCSK9-targeted treatments.
Methods
This regional observational registry included consecutive patients from nine referral centers initiated on PCSK9i or siRNA therapy according to clinical guidelines. The primary objective was to assess LDL-c reduction variability based on BT modifications and patient adherence. Adherence was quantified using the Adherence in Chronic Diseases Scale (ACDS), classifying patients into high (≥27), intermediate (21–26), or low (≤20) groups. Patients were also categorized by BT trajectory: those who reduced or stopped background drugs (BT-), those who maintained stable doses (BT=), and those who intensified oral therapy (BT+). Statistical analyses were performed using R software, with significance defined as p<0.05 (two-tailed).
Results
The study cohort comprised 403 patients (70% male, mean age 65 ± 11 years) followed for a median of 15 months. Reported adherence was high in 38%, moderate in 43%, and low in 19% of the population. Secondary prevention was the indication for 71% of patients (65% previous myocardial infarction, 6% previous stroke/TIA), while 27% met the criteria for statin intolerance. While the average LDL-c reduction was -48% across the entire cohort, results differed widely according to adherence (Figure 1 depicts the waterfall plot of all patients). Patients who decreased or discontinued their background therapy (BT-) experienced a significantly lower LDL-c drop (-28%) compared to those with stable (BT=, -58%) or intensified (BT+, -65%) background regimens (p<0.001, Figure 2).
Conclusions
The clinical effectiveness of PCSK9i and siRNA therapy is strictly dependent on the maintenance of background statin and ezetimibe adherence. Although highly adherent patients achieve LDL-c reductions consistent with phase III clinical trials, the perceived benefit of these advanced therapies is significantly diminished in the real world when oral background therapy is scaled back. These findings underscore the necessity of patient education to ensure that new injectable therapies supplement, rather than replace, established oral lipid-lowering regimens.Figure 1Figure 2